DMEJ

Duke Medical Ethics Journal

The Role, Impact, and Legacy of Thalidomide in Manufacturing Health Inequalities

By: Heiley Tai

I. The Origins of Thalidomide

The drug thalidomide was first developed in 1953 in Switzerland and put on the market in 1957 by the German pharmaceutical company Chemie-Grünenthal [7]. It was marketed as a nonaddictive alternative to barbiturates, which have sedative properties. Thalidomide, viewed as a panacea or “wonder drug,” eventually made it out of the German market and went on to be distributed in 46 countries [16]. One of its most common uses was in alleviating symptoms of morning sickness and nausea in pregnant women. By 1959, there was a startling number of children being born with severe physical birth defects. It wasn’t until 1961 that research was able to link thalidomide ingested by pregnant mothers to the subsequent malformations observed in their children, and thalidomide was taken off the market sooner [7]. There are an estimated 10,000 children born who were affected by thalidomide. However, some victims either didn’t make it to term or died early in life, though the connection to thalidomide wasn’t made until later on. The experience of thalidomide by surviving children also varies from person to person, suggesting that the figure of affected individuals is a low estimate.

II. Thalidomide’s Chemical Properties and Effects

Thalidomide’s molecular formula is C13H10N2O4, making it a relatively small and unassuming structure [15]. It exists in two unique spatial arrangements, thus it can be further classified as (R) or (S). The prescription medication distributed during this time comprised a mixture of these two forms. The (R) form is known to have sedative and hypnotic properties while the (S) form is known to be teratogenic - if someone is exposed to the (S) form of thalidomide during pregnancy, it can interfere with normal fetal development and lead to congenital disorders in the child. The properties of both forms put together, as was the case in the 20th century commercial drug, simultaneously treated nausea and morning sickness in pregnant women while causing physical malformations in their children [11].

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Figure 1. Thalidomide enantiomers, mirror-image forms of the same molecule that can have vastly different physical and chemical properties [8].

One of the hallmarks of thalidomide embryopathy is visible prior to birth. Phocomelia is a congenital abnormality in which the limbs appear shortened or absent and extremities are instead attached at the trunk of the body. Affected individuals may also experience damage to the ears, eyes, and internal organs. Cardiovascular system anomalies have been frequently reported. It’s important to note that despite these patterns, each case is still unique [14].

Figure 2. X-ray scans of an infant suffering from phocomelia [5].

III. Important Industry Players

The head of research responsible for pushing this drug out at Chemie-Grünenthal (known today as simply Grünenthal), Dr. Heinrich Mückter, was a Nazi war criminal who was a perpetrator of human experimentation in concentration camps in Poland. He fled back to Germany before he could face trial, and was welcomed by Chemie-Grünenthal [3, 13]. The Grünenthal website, which has a small subpage addressing its role in the thalidomide tragedy, makes no mention of this history [10]. Although Mückter was aware of the potential harms associated with thalidomide, he still went forth to put thalidomide on the market [3].

While thalidomide was marketed as a completely safe drug to alleviate the symptoms of morning sickness, it had been approved in Germany without any clinical trials involving pregnant women [13]. As a result, German children are estimated to comprise 5,000 of the 10,000 children affected globally [2]. While the use of thalidomide spread relatively quickly, the application for sale in the U.S. was denied FDA approval thanks to the work of Dr. Frances Kelsey [13], who cited safety concerns due to reports of adults experiencing peripheral neuropathy as a side effect of thalidomide as well as a lack of testing in pregnant women. However, this doesn’t mean that American children were entirely spared the effects of thalidomide.

Drug companies Smith, Kline & French (now known as GlaxoSmithKline) and Richardson-Merrell (now known as Sanofi) conducted rushed and sloppy clinical trials in the U.S. with the aim to push the drug into the market for sale as quickly as possible, being so negligent as to keep lackluster records of which doctors they distributed the trial drug to and which patients actually received dosages. Neither company was transparent in their intentions for

the trial when distributing thalidomide to doctors. On the contrary, the marketing departments at these companies appeared to be more thorough in their efforts than the actual science and research. Richardson-Merrell even went as far as to encourage doctors to not keep track of which patients took thalidomide during the trial [13].

Nine employees and senior executives at Grünenthal were put to trial, though none were convicted. Instead, the company along with the German government paid millions of dollars to families and support foundations [2]. And although thalidomide was given to 20,000 Americans in clinical trials sponsored by Smith, Kline, & French and Richardson-Merrell, the U.S. federal government never ended up pressing charges against either company due to limited evidence. It was concluded that Smith, Kline & French had acted legally, and although the Department of Justice was building a case against Richardson-Merrell, it ultimately did not pursue criminal prosecution [12, 13].

“The thalidomide tragedy embodies the role of the pharmaceutical industry in ‘creating’ bodies of people who are disadvantaged in medicine and healthcare.”

IV. Lessons and Conclusions

Thalidomide was only on the market for 4 years, having been withdrawn by Chemie-Grünenthal in 1961. However, the damage had already been done in this short period. Thalidomide resulted in 10,000 known cases worldwide of thalidomide embryopathy with 5,000 of those cases being in Germany [2]. The drug was marketed as being completely safe, and even though the FDA never approved the thalidomide for sale in the U.S., an unknown number of pregnant women ingested the drug in clinical trials and gave birth to similarly affected infants. Because many doctors were either ignorant to or knowingly withheld information about the drug from their patients, it’s possible that thousands more were affected and will never find out. Sadly, there is no silver lining, as the mothers who knew they had taken thalidomide during their pregnancies often experienced an insurmountable level of guilt, sometimes to the effect that they only informed their children on their deathbeds [2].

In the U.S., during investigations of Richardson-Merrell, the FDA has also failed survivors by mishandling cases of thalidomide toxicity. The FDA prioritized only those cases that would aid in the prosecution of the corporation, and neglected all other evidence that wouldn’t explicitly help them build a case. In effect, the FDA failed to conduct a proper and thorough investigation, allowing more victims to fall through the cracks due to a lack of effort to investigate. Mothers who had reason to suspect their child was affected were ignored if their doctors weren’t named in Richardson-Merrell’s records of the trial - which were very likely not comprehensive [12].

All of this has ramifications for survivors. Increasingly few doctors are experienced with treating thalidomide survivors. This includes routine examinations, because they may not be familiar with taking the pulse or blood pressure of someone whose limbs never developed properly. Thalidomide has also been known to cause side effects and abnormalities that aren’t externally visible. Internal organ and nerve/vessel damage can also make thalidomide survivors more vulnerable to complications from otherwise low-risk operations and surgeries [2]. Their health-related expenses tend to be much higher as electric wheelchairs, adapted vehicles, and specialized medical devices to assist with sensory deficits don’t come cheap [1]. Some survivors report that their daily routines are more difficult to manage due to lifelong conditions such as chronic pain and physical disability [9]. Others find themselves struggling to find and keep jobs, making it more difficult to offset the costs of living with their condition. In the UK, it’s reported that over 40% of individuals affected by thalidomide experience such difficulties. They face everyday mobility difficulties, and have to fight tooth-and-nail in lawsuits against giant corporations to receive even the slightest compensation. It was only after a lengthy legal battle in 1968 that children and families affected by thalidomide in the UK, obtained any kind of compensation from Distillers, the distributor at the time. Even so, the compensation paid out to each victim totaled only 40% of the assessed damages caused by the drug [1].

V. Thalidomide Today

The thalidomide tragedy remains relevant today for a multitude of reasons - the primary one being that it was entirely preventable. Marginalization of groups of people can be induced with malicious or negligent intentions from corporations or institutions. The thalidomide tragedy embodies the role of the pharmaceutical industry in “creating” bodies of people who are disadvantaged in medicine and healthcare, and the lack of consequences for pharmaceutical perpetrators. Of course, the responsibility doesn’t fall exclusively on drug makers who peddle misleading narratives or lies to boost sales, but also governing bodies who fail to pursue justice.

While the thalidomide disaster has sowed fear and mistrust towards medications and pharmaceutical companies, thalidomide itself isn’t inherently toxic. It’s important to note that thalidomide is teratogenic, and that the primary population at risk for adverse events and outcomes are those who are pregnant.

Thalidomide was, and still is, approved for treating cancer and leprosy [11], with new restrictions regarding pregnant women. Given its turbulent history, one would expect heavy regulations surrounding the use of this drug on a global scale, due to the global nature of its impact.

Recent research has shed light on whether the continued use of thalidomide is sufficiently controlled, particularly in countries like Brazil where leprosy is endemic and control efforts are still underway. Thalidomide is also prescribed for a variety of other ailments, including HIV-AIDS symptoms and lupus. In light of the global tragedy, there have been statewide efforts to reform the distribution and documentation of the drug, putting thalidomide back on the market in Brazil, just three years after being banned in 1962. Currently, the public healthcare system maintains responsibility for thalidomide distribution. The government has also made policy updates requiring all patients capable of bearing children to undergo pregnancy testing and ensuring that facilities and doctors administering thalidomide are properly registered and subject to annual evaluations. However, from 1969 to 1995, Brazil accounted for 33 out of 34 cases of thalidomide-related malformations in South America. While it appears that the thalidomide was prescribed for its intended use for treatment of leprosy, pregnant women were still somehow gaining access to this drug. There have been cases confirmed as recently as 2018 [4].

The world has learned from the thalidomide tragedy. This event directly resulted in more stringent regulations and testing protocols for new drugs and therapeutics before they’re allowed on the market. The study of toxicology as a whole developed from this single tragedy [9]. And yet, there is still reason to worry about and continue research on the impacts of thalidomide, with extra scrutiny towards its allocation and usage in the modern day. Because toxicology and clinical trials have made leaps and bounds since this happened, it’s alarming that children affected by thalidomide are still being born. In Brazil, survivors experiencing physical disabilities are entitled to a lifetime pension and indemnity from the federal government [4]. However, compensation does not address a problem that is rooted in a lack of public awareness, medical transparency, and effective government regulation.

Review Editor: Eric Wang
Design Editor: Heiley Tai

References